Is ABCG5 p.Leu391Phe (c.1171C>T) pathogenic?

ABCG5 p.Leu391Phe (c.1171C>T) is classified Uncertain significance in ABCG5 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0799); Ultra-rare (popmax 0.0653%, afr); Associated with sitosterolemia 2.

What condition is associated with ABCG5 p.Leu391Phe (c.1171C>T)?

ABCG5 p.Leu391Phe (c.1171C>T) is associated with sitosterolemia 2, sitosterolemia (ClinVar).

How common is ABCG5 p.Leu391Phe (c.1171C>T) in the general population?

ABCG5 p.Leu391Phe (c.1171C>T) is ultra-rare (popmax 0.0653%, afr) (gnomAD).

How is Sitosterolemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCG5 p.Leu391Phe (c.1171C>T)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

ABCG5 p.Leu391Phe

c.1171C>T · rs148997255 · VCV597032

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0653%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia 2

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.46	acceptor gain · deltas
Pangolin	Δ0.56	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -1.4	GERP -3.9
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	17.76	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0653% African / African-American · 49/75,060 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0455%

Overall 0.00502% 81/1,614,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0653%	1,532
Admixed American	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.0176%	5,683
European (non-Finnish)	8.47e-05%	1,180,036

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCG5
Protein: p.Leu391Phe
Coding: c.1171C>T
MANE Select: NM_022436
dbSNP: rs148997255
Type: single nucleotide variant
Location: chr2:43824066 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 8 PDB
Residue 391: the abc transmembrane type-2 domain; an α-helix

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sitosterolemia

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 p.Leu391His Uncertain significance ★ ⚠ same residue
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.634+1G>C Likely pathogenic ★★ same condition
ABCG5 c.904+1G>A Pathogenic ★★ same condition
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abcg5-p-leu391phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown